Diagnostic preparations



Patented June 24, 1947 UNITED STATES PATENT OFFICE DIAGNO STIC PREPARATIONS Hermann Vollmer, New York, N. Y.

No Drawing. Application March 9, 1945, Serial No. 581,940

Claims. 1

This application is a continuation-in-part of my co-pending U. S. patent application Serial No. 427,391, filed January 19, 1942, and entitled Composition of matter.

My present invention relates to new means, particularly preparations, for administering diagnostic allergenic substances through the skin and particularly to making tests on human beings to determine the presence or absence of tuberculous infection and the allergic reaction to various allergenic substances.

It is an object of my invention to provide preparations, by which diagnostic substances, particularly allergenic substances, can be administered and allergy and other tests carried out easily and conveniently.

A further object of my present invention con sists in providing new compositions of matter, 1. e. preparations for administering diagnostic, particularly allergenic substances, through the skin, and for carrying out the above mentioned tests.

Still a further object of my invention consists in providing means enabling continuous observation of the reaction to the diagnostic, e. g. allergenic substances applied to the skin during a considerable period of time after administration.

With the above objects in view, each of the new diagnostic preparations proposed by me herewith comprises an emulsion of a solution of a film forming substance in a volatile solvent adapted to form after volatilization of said volatile solvent a flexible solid'film, of a non-volatile fluid vehicle substance being insoluble in the said solution of said film forming substance, and of the diagnostic, preferably allergenic substance tobe administered incorporated in and retained by the above mentioned non-volatile fluid vehicle substances. I wish to note that the term flexible solid film is intended to define a film of a solid, i. e. non-fluid substance, which is adapted to bend and to follow the movement of the skin to which it adheres after application. I wish also to stress that the term film forming substance, as used above and in the following description and claims, is intended to cover only substances which-after volatilization of a solvent in which they are dissolved-form a flexible solid film of the above defined type.

It should be stressedthat it is of greatest importance for the purposes of the present invention to use an emulsion-and not a solutionof the adhesive substance, 1. e. of the solution of the film forming substance in a volatile solvent, and of the diagnostic substance to be administered, i. e. of the non-volatile fluid vehicle substance being insoluble in the said solution of the film forming substance and containing the diagnostic allergenic substance to be administered. When this diagnostic emulsion is applied to the human skin, th solvent evaporates and the film forming substance forms a tough, elastic coating adhering to that skin portion to which the preparation has been applied; this elastic film coating consists of a network of fibers formed by evaporation of the solvent and including the droplets of the still fluid diagnostic substance, i. e; of th non-volatile fluid vehicle substance containing the diagnostic allergenic substance to be administered.

Sometimes it is advisable to use a solution of a transparent adhesive film forming substance which after drying forms an adhering patch-like transparent film coating firmly adhering to the human skin and containing fiuid droplets of the diagnostic substance, 1. e. the non-volatile fluid vehicle substance including the diagnostic allergenic substance to be brought into intimate contact with the skin; such a transparent film coating enables observation of the skin reaction to the diagnostic allergenic test substance during an extended period of time.

For dissolving the adhesive film forming substance, I preferably use a liquid solvent rapidly volatilizing when exposed to air; thus, a firmly adhering, patch-like film coating can easily be produced by simply applying to the skin a small amount of a diagnostic emulsion of the type defined above and allowing the thus applied emulsion to dry for a short period of time, c. g. two or three minutes. As mentioned above, during such drying the solvent contained in the film forming solution, forming part of the applied diagnostic emulsion, will evaporate and the thus solidified film forming substance will create an adhesive patch-like film coating firmly adhering to the human skin; as mentioned above, this dried film coating will contain within its network small fluid droplets of the non-volatile vehicle substance containing th diagnostic allergenic test substance to be administered. It is evident that these small fluid droplets will be excellent vehicles for bringing th allergenic substance contained in the same into close contact with the skin, since due to their fluid state, they will not only maintain their diagnostic allergenic ingredients in active efficient state but also be easily absorbed by the skin together with these: allergenic ingredients. Contrary thereto,'if a diagnostic allergenic substance is dissolved with a film forming substance in a volatile solvent and applied, evaporation of the volatile solvent will create a film which will contain the allergenic ingredients in dry, nonactive, non-efiicient state. Such dry particles of the allergenic substance can hardly be absorbed by the skin and will be practically inefiective, i. e. create no allergenic test reactions on the skin.

Sometimes, it is somewhat difiicult to make a stable emulsion of the adhesive film forming substance diluted in the volatile solvent and the non-volatile fluid vehicle substance being insoluble in this film forming solution and containing the diagnostic allergenic substance to be applied; in such cases, it has proved advantageous to add to the diagnostic emulsion a wetting agent of well-known type. Such agents have the effect of reducing the interfacial tension between the two phases forming the emulsion, thereby increasing their capacity to form stable emulsions of the required type.

The most varied adhesive film forming substances may be used for the purposes of the present invention; their main characteristics have to be that they are soluble in a volatile liquid, that they are adapted toform after drying a preferably tough, elastic film coating adhering to the human skin, and finally that they have no harmful effects when applied to the human sla n for an extended period of time.

An adhesive substance with which I obtained very good results is collodium dissolved in a mixture of alcohol and ether. To this solution the diagnostic substance is added, then the thus obtained mixture emulsified and applied to the skin of the patient.

I also made experiments with other adh'esive film forming substances and volatile solutions thereof and found that certain nail polishes, particularly thos which are resin solutions, may very well be used as film forming adhesives for the purposes of the present invention. Other film forming substances adapted for these purposes are for instance polyvinyl chloride-vinyl acetate copolymer, acetal from polyvinyl alcohol and butyraldehyde, cellulose acetate butyrate, ethyl cellulose and other water insoluble cellulose esters and ethers, and other film forming substances, particularly resins, if the same have the above listed characteristics. For forming the required solutions of these substances various volatile solvents, e. g. ethyl acetate, dimethyl ketone, cyclohexanone, toluene, benzene, ethylene dichloride and nitroparaifines, such as nitroethane, may be used. It should be stressed that the term film forming solution or solution of a film forming substance as used above and in the following description and claims is always intended to define a solution of such a film forming substance in a volatile solvent.

As mentioned above, various diagnostic substancesmight be administered with aid of the new means proposed herewith. Thus, for instance, I have obtained very good results in carrying out allergy patch tests with various allergenic substances, e. g. tuberculin allergen, navy bean-allergen, peanut allergen, mustard allergen, Whitefish allergen and horse serum allergen, in the way described above by me.

In accordance with a preferred embodiment of my present invention, the preferably glycerinated allergenic substance, e. g. glycerinated tuberculin, is intimately emulsified with an adhesive film forming, e. g. collodium solution ofthe above described type; if necessary, a small percentage of a wetting agent, as a dioctyl ester of sodium sulfosuccinic acid, and various petroleum sulfonates, may be added too. The thus prepared adhesive diagnostic emulsion is applied in form of small patches to the skin of the person to be examined and the emulsion allowed to dry, forming thus one or more small film patches firmly adhering to the skin. Each of these film patches consists of an elastic coating of the adhesive film forming material, e. g. collodium, containing small fluid droplets of the non-volatile vehicle substance including the allergenic substance, e. g. tuberculin, to be applied.

As mentioned above, various vehicle substances may be used. If glycerinated allergenic substances are used, the vehicle substance will be an aqueous glycerine solution consisting of about equal parts of glycerine and water. However, it is also possible to use other vehicle substances, for instance such as propylene glycol, sorbitan and others. Their main common characteristics have to be that they are non-volatile and insoluble in the solution of the film forming substance with which they have to form an emulsion. Furthermore, I wish to stress that it is advantageous to use vehicle substances which are to a certain degree hygroscopic, as for instance glycerine and glycerinated substances; thi will prevent drying and evaporation of the fluid droplets of these vehicle substances occluded in the film patches after application of the same to the skin.

In this connection, I wish to stress that the required insolubility of the vehicle substances in the film forming solutions is of course a relative one; this means that for the purposes of the present invention such an amount of a non-volatile vehicle substance has to be admixed to the film forming solution that the same is insoluble in this film forming solution and forms an emulsion with the same. Thus, for the purposes of the present invention, it is only of importance that the proportion, i. e. relation between the percentage of film forming solution and the percentage of non-volatile vehicle substance, be chosen in such a manner as to form an emulsion and not a solution.

It is evident that there will be certain film formin solutions and non-volatile vehicle substances which will always form emulsions irrespectively of their relative percentages; however, it should be stressed that for the purposes of my present invention I might also use combinations of film forming solutions and vehicle substances which when mixed under certain circumstances, 1. e. in certain proportions, form solutions, and when combined under different circumstances, 1. e. in certain other proportions, form emulsions. Of course, if such substances are used, only such compositions of these film forming solutions and vehicle substances which form emulsions form part of my present invention. Thus, the term insoluble as used in the following description and claims is intended to define such vehicle substances which when mixed under certain circumstances, e. g. in certain proportions with the film forming solutions, are insoluble in these solutions and form emulsions with the same. I have found that quite a number of non-volatile vehicle substances form solutions with the film forming solutions when added in a small proportion to the same, but form emulsions with these film forming solutions when added in higher proportions, e. g. to above 20%.

I wish also to note that preferably in all diagnostic emulsions used by me the film forming solutionstform the continuous phase and the nonvolatile. fluid; vehicle. substances containing the diagnostic allergenic substances form the noncontinuousphase of the emulsion, i. e. these nonvolatile fluid vehicle substances containing the diagnostic allergenic substances are emulsified in the film forming solutions.

A: diagnostic emulsion for determining the presence: or absence of tuberculous infection which I have found particularly efiicient consists of equal parts of collodium dissolved in a volatile liquid, e. g. alcohol and/or ether, glycerinated tuberculin and traces of a dioctyl ester of sodium sulfosuC- cinic acid asawetting agent.

' My present invention will be illustrated by the following examples; however, I Wish to stress that my invention is not intended to be limited by the same. In all these examples the diagnostic preparations, e. g. diagnostic allergenic emulsions, are made in the same Way, namely by preparing the film forming solution and the allergen containing vehicle solution and intimately mixing the same with each other in such proportions as toform the required diagnostic emulsion; in all these emulsions, however, the ingredients and their percentages are different. Therefore, in order to simplify description of the various examples I will in the following only define their composition without describing in detail the mode of preparation of the same.

Example I A diagnostic preparation consisting of an emulsion of equal parts by volume of glycerinated tuberculinv and a collodium solution. The glycerinated tuberculin is a tuberculin containing aqueous glycerine solution composed of equal parts by volume of glycerine and Water.

Example I] A diagnostic preparation consisting of an emulsion of equal parts by volume of a tuberculinsorbitan solution and a collodium solution. The tuberculin-sorbitan solution is composed of equal parts by volume of concentrated aqueous tuberculin solution and sorbitan.

Example III A diagnostic preparation consisting of an emulsionof five part by volume of glycerinated tuberculin and six parts by volume of a ten per cent solution of aceta-l from polyvinyl alcohol and butyraldehyde in ethyl acetate. The glycerinated tuberculin is a. tuberculin containing aqueous glycerine solution composed of 60% by volume of Water and 40% by volume of glycerine.

Example IV A diagnostic preparation consisting of an emulsion of equal parts by volume of glycerinated tuberculin and a ten per cent solution ofcellulose acetate butyrate in ethyl acetate. The glycerinated tuberculin is a tuberculin containing aqueou glycerine solution composed of equal parts by volume of Water and glycerine.

Example V A diagnostic preparation consisting of an emulsion of four parts by volume of glycerinated tuberculin and seven parts by volume of a ten per cent solution of polyvinyl chloride vinyl acetate copolymer in ethyl acetate. The glycerinated tuberculin is a tuberculin containing aqueous glycerine solution composed of 75% by volume of water and 25% by volume of glycerine.

Example VI A diagnostic preparation consisting of an emulsionof equal parts byvolume of glycerinated tuberculin and a resin solution. The glycerinated tuberculin is a tuberculin containing aqueous glycerine solution composed of equal partsby volume of water and glycerine.

Example VII Example VIII A diagnostic preparation consisting of an. emulsion of five parts by volume of glycerinated navy bean allergen and six parts by volume of a 5% solution of polyvinyl chloride vinyl acetate copolymer in ethyl acetate. The glycerinated navy bean allergen is an aqueous glycerine solution containing navy bean extract.

Example IX Thi diagnostic preparation is similar to the one described in Example VIII, the only difference being that the five parts by volume of glycerinated navy beanallergen are emulsified in five parts by volume of a five per cent solution of acetal from polyvinyl alcohol and butyraldehyde in ethyl acetate.

Example X This diagnostic preparation is also similar to the one described in Example VIII, the only difference being that the five parts by volume of glycerinated navy bean allergen are emulsified in six parts by volume of a five per cent solution of a cellulose acetate butyrate in ethyl acetate.

Example XI This diagnostic preparation is also similar to the one described in Example VIII, the only difference being that the five parts by volume of glycerinated navy bean allergen are emulsified in. five parts by volume of a collodium solution, Traces of a Wetting agent may be added.

Example XII This diagnostic preparation is similar to the one described in Example VIII with the only difference that instead of glycerinated navy bean allergen, glycerinated peanut allergen is emulsified in the film forming solution disclosed in that example.

Example XIII This diagnostic preparation is identical to the one disclosed in Example I With the only difference that traces of a wetting agent are added.

Example XIV This diagnostic preparation is identical to the one described in Example II with the only difference that instead of a tuberculin-sorbitan solution a sorbitan solution of another allergen, e. g. navy bean allergen, mustard allergen, white fish allergen, horse serum allergen, or similar allergen, is used.

7 Example XV This diagnostic preparation is identical to that described in Example VII with the only difference that instead of a tuberculin-propylene glycol solution a. propylene glycol solution of another allergen of the type defined in Example XIV is used.

It will be understood that each of the elements described above, or two or more together, may also find a useful application in other types of therapeutic emulsions differing from the types described above.

While I have illustrated and described the invention as embodied in diagnostic emulsions, I do not intend to be limited to the detail shown, since various modifications and changes may be made without departing in any way from the spirit of my invention.

Without further analysis, the foregoing will so fully reveal the gist of my invention that others can by applying current knowledge readily adapt it for various applications without omitting features that, from the standpoint of prior art, fairly constitute essential characteristics of the generic or specific aspects of this invention and, therefore, such adaptations should and are intended to be comprehended within the meaning and range of equivalence of the following claims.

What I claim as new and desire to secure by Letters Patent is:

1. Diagnostic preparation consisting of an emulsion of a solution of a film forming substance in a volatile solvent adapted to form after volatilization of said volatile solvent a flexible solid film, of a non-volatile fluid vehicle substance being insoluble in said solution of said film forming substance, and of a diagnostic substance adapted to create a skin reaction incorporated in and retained by said non-volatile fluid vehicle substance.

2. Diagnostic preparation consisting mainly of an emulsion of a solution of pyroxylin in a volatile solvent, of a non-volatile liquid vehicle substance being insoluble in said pyroxylin solution, and of a diagnostic allergenic substance incorporated in and retained by said non-volatile liquid vehicle substance.

3. Diagnostic preparation comprising an emulsion of a solution of a film forming resinous substance in a volatile solvent, of a glycerine-water solution serving as vehicle substance, and of an allergenic substance incorporated in said glycerine-water solution.

4. Diagnostic preparation comprising an emulsion of a solution of pyroxylin in a volatile solvent, of a glycerine-water solution, and of a liquid allergenic substance incorporated in said glycerine-water solution.

5. Diagnostic preparation comprising an emulsion of a solution of a film forming resinous substance in a volatile solvent forming the continuous phase of said emulsion, of a non-volatile liquid vehicle substance consisting of about equal parts by volume of glycerine and water emulsified in said solution of said film forming resinous substance and containing an allergenic substance.

6. Diagnostic preparation comprising an emulsion of a solution of pyroxylin in a volatile solvent forming the continuous phase of said emulsion and of a non-volatile liquid vehicle substance consisting of about equal parts by volume of glycerine and water, said non-volatile vehicle substance containing an allergenic substance and being emulsified in said pyroxylin solution forming the non-continuous phase of said emulsion.

7. Diagnostic preparation consisting mainly of an emulsion of a solution of pyroxylin in a volatile solvent forming the continuous phase of said emulsion, and of non-volatile glycerinated tuberculin incorporated in said collodium solution in such proportion as to be insoluble in the same and to form the non-continuous phase of said emulsion.

8. Diagnostic preparation consisting mainly of an emulsion of pyroxylin dissolved in alcohol and ether, and of a non-volatile liquid vehicle substance being insoluble in said dissolved collodium, and of an allergenic substance incorporated in and retained by said non-volatile liquid vehicle substance.

9. Diagnostic preparation consisting of an emulsion of a solution of a film forming substance in a volatile solvent forming the continuous phase of said emulsion and adapted to form after volatilization of said volatile solvent a flexible solid film, and of a non-volatile hygroscopic liquid vehicle substance being insoluble in said solution of said film forming substance, and of a diagnostic substance adapted to create a skin reaction incorporated in and retained by said non-volatile hygroscopic liquid vehicle substance.

10. Diagnostic preparation consisting mainly of an emulsion of a solution of pyroxylin in a volatile solvent forming the continuous phase of said emulsion and of a non-volatile solution of glycerine, water, tuberculin and a wetting agent being insoluble in said collodium solution and forming the non-continuous phase of said emulsion.

HERMANN VOLLMIER.

tEFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 304,729 Hentz Sept. 9, 1884 2,190,745 Vollmer Feb. 20, 1940 2,304,817 Grozin Dec. 15, 1942 2,278,339 Vollmer Mar. 31, 1942 FOREIGN PATENTS Number Country Date 98,419 Austria Nov. 10, 1924 OTHER REFERENCES (Copy 

